This invention relates generally to a novel process for the preparation of 2-halo-5-halomethylpyridines. In a more particular sense, a preferred embodiment of this invention relates to such a process which includes cyclocondensing certain 2-halo-2-halomethyl aldehydes or ketones to form corresponding 2-halo-5-halomethylpyridines.
The importance of 2-chloro-5-chloromethylpyridines as pharmaceutical and agricultural intermediates has been well established. For example, 2-chloro-5-chloromethylpyridine can be used for synthesis of herbicide as described by European Patent 163855 (December 1985). Traditionally, 2-chloro-5-chloromethylpyridines have been prepared by chlorination of 2-chloro-5-methylpyridines or 2-chloro-5-hydroxymethylpyridines. For instance, conversion of 2-chloro-5-methylpyridine to 2-chloro-5-chloromethylpyridine was described in U.S. Pat. No. 4,778,896 to Gallenkamp. The preparation of the 2-chloro-5-methylpyridine starting material in this reaction has itself been the subject of several studies. U.S. Pat. No. 4,897,488 to Gallenkamp et al., European Patent Application 0324174 (December 1988), and German Patent Document DE 3839332 (May, 1990) relate to methods of converting 3-methylpyridine through its N-oxide derivative to 2-chloro-5-methylpyridine, along with isomeric 2-chloro-3-chloromethylpyridine which is difficult to separate. European Patent 108483 describes preparation of 2-chloro-5-methylpyridine from acyclic intermediate by ring synthesis, which includes a sequence of enamine formation, cycloaddition, ring opening, cyclization, oxidative aromatization and finally chlorination.
Conversion of 2-chloro-5-hydroxymethylpyridine to 2-chloro-5-chloromethylpyridine is described in J. Heterocyclic Chem., 1979, 15, page 333, and U.S. Pat. No. 4,576,629 to Morland et al. The required intermediate 2-chloro-5-hydroxymethylpyridine was prepared from 6-chloro-3-pyridinecarboxylic acid by a sequence of transformations.
U.S. Pat. Nos. 4,990,622 and 4,958,025 both to Jelich describe a synthesis of 2-chloro-5-chloromethylpyridine from nicotinic acid through a five-step process. European Patent Application 0393453 (April 1990) describes a similar process, except starting from 3-dichloromethylpyridine.
All of these known processes of preparing 2-chloro-5-chloromethylpyridine have the disadvantages of low selectivity, prolonged and extensive reaction sequences, or harsh reaction conditions. Some also require the modification of substituent(s) on an existing pyridine ring.
Accordingly, there exists a continuing need and demand for processes for producing 2-halo-5-halomethylpyridines which are simple yet selective, and which can be conducted employing reaction conditions conducive to production on a reasonable scale with reasonable safety and process requirements. The applicants' invention addresses these needs.